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Bromide, the first effective therapy for epilepsy, is not commonly prescribed today but has been advocated by some pediatric neurologists for the treatment of intractable seizures in children. We report a 17-year-old female patient with intractable epilepsy who insidiously developed bromism while on treatment with triple bromide elixir. We review the clinical presentation, diagnosis, pathophysiology, and management of bromism.

Several cytokines have been reported to have hepatoprotective properties in animal models of acetaminophen toxicity. To investigate the relationships of cytokines and toxicity in acetaminophen overdose, blood samples were collected from patients following acute ingestions of acetaminophen. Samples for cytokine analysis were collected at the time of routine clinical monitoring in 111 patients (90 females; mean age 13.6 years). Plasma concentrations of interleukin 6, interleukin 8, interleukin 10, and monocyte chemoattractant protein 1 were analyzed by enzyme-linked immunosorbent assay. Patients were stratified by toxicity severity, defined by the maximal values of hepatic transaminase elevation. Levels of interleukin 6, interleukin 8, and monocyte chemoattractant protein 1 were higher in patients with serum alanine aminotransferase > 1000 IU/L, and monocyte chemoattractant protein 1 had the strongest association with toxicity. Monocyte chemoattractant protein 1 values were higher in patients with greater delays in N-acetylcysteine treatment and in patients with higher values of prothrombin time. Monocyte chemoattractant protein 1 elevation in acetaminophen overdose may represent an innate, immunomodulary response of the liver to earlier events in the toxicity. An understanding of the role of cytokine responses in acetaminophen overdose may be relevant to the future development of new therapies for acetaminophen toxicity.

Background & Aims: Acetaminophen toxicity is the most common cause of acute liver failure (ALF) in the United States and Great Britain, but may be underrecognized in certain settings. Acetaminophen–protein adducts are specific biomarkers of drug-related toxicity in animal models and can be measured in tissue or blood samples. Measurement of serum adducts might improve diagnostic accuracy in acute liver failure (ALF) patients. Methods: We measured serum acetaminophen–protein adducts using high-pressure liquid chromatography with electrochemical detection in coded sera of 66 patients with ALF collected prospectively at 24 US tertiary referral centers. Samples were included from 20 patients with well-characterized acetaminophen-related acute liver failure, 10 patients with ALF owing to other well-defined causes, 36 patients with ALF of indeterminate etiology, and 15 additional patients without ALF but with known acetaminophen overdose and minimal or no biochemical liver injury. Results: Acetaminophen–protein adducts were detected in serum in 100% of known acetaminophen ALF patients and in none of the ALF patients with other defined causes, yielding a sensitivity and specificity of 100%. In daily serial samples, serum adducts decreased in parallel with aminotransferase levels. Seven of 36 (19%) indeterminate cases demonstrated adducts in serum suggesting that acetaminophen toxicity caused or contributed to ALF in these patients. Low adduct levels were present in 2 of 15 patients with acetaminophen overdose without significant liver injury. Conclusions: Measurement of serum acetaminophen–protein adducts reliably identified acetaminophen toxicity, and may be a useful diagnostic test for cases lacking historical data or other clinical information.

Injuries from piercing or cutting instruments or objects are commonly seen in the pediatric emergency department. In this study, we present the epidemiology of piercing injuries resulting in hospitalization. Medical records for a one-year period with E-codes 920.0-920.9 were reviewed for victim-related demographic data, anatomic injury location, vehicle of injury, treatment, and hospital charges. The Abbreviated Injury Scale (AIS) was used to ascertain injury severity. The most common vehicles of injury were glass (n = 24, 34%), nails (n = 11, 16%), and needles (n = 10, 14%). The median AIS score was significantly higher for hand injuries compared to the sample median AIS. Piercing injuries from consumer-related products were associated with the highest AIS scores (median = 2.5). Although the mean AIS for all injuries was only 1.5, these injuries resulted in significant costs, with a mean hospitalization charge of $3884 +/- 3528. Surgical procedures under general anesthesia were required in 81% of the patients.

Previous data have indicated that activated macrophages may play a role in the mediation of acetaminophen toxicity. In the present study, we examined the significance of superoxide produced by macrophages by comparing the toxicity of acetaminophen in wild-type mice to mice deficient in gp91phox, a critical subunit of NADPH oxidase that is the primary source of phagocytic superoxide. Both groups of mice were dosed with 300 mg/kg of acetaminophen or saline and sacrificed at 1, 2, 4 or 24 h. Glutathione in total liver and in mitochondria was depleted by approximately 90% at 1 h in wild-type and knock out mice. No significant differences in toxicity (serum transaminase levels or histopathology) were observed between wild-type and mice deficient in gp91phox. Mitochondrial glutathione disulfide, as a percent of total glutathione, was determined as a measure of oxidant stress produced by increased superoxide, leading to hydrogen peroxide and/or peroxynitrite. The percent mitochondrial glutathione disulfide increased to approximately 60% at 1 h and 70% at 2 h in both groups of mice. Immunohistochemical staining for nitrotyrosine was present in vascular endothelial cells at 1 h in both groups of mice. Acetaminophen protein adducts were present in hepatocytes at 1 h in both wild-type and knock out animals. These data indicate that superoxide from activated macrophages is not critical to the development of acetaminophen toxicity and provide further support for the role of mitochondrial oxidant stress in acetaminophen toxicity.

With the removal of cisapride from the U.S. market, practitioners have increasingly used other medications, such as metoclopramide, to treat gastroesophageal reflux in pediatric patients. We describe the case of a neonate who developed methemoglobinemia after receiving metoclopramide at doses slightly above the recommended age-appropriate dosage. Health care providers should be aware of this potentially serious side effect in young infants who receive this medication.

The design of studies to evaluate the efficacy of acid-lowering drugs in children differs significantly from study designs in adult populations. Efficacy measurements may be less extensive than those used in adult studies because of limitations that exist secondary to concerns for patient safety, parental and institutional review board acceptance of efficacy end points, and existing standards of care within the pediatric gastroenterology community. Study designs involving patients who would routinely receive acid-lowering therapy have been successfully used to characterize the pharmacokinetics and pharmacodynamics of acid-lowering therapies (H 2 receptor antagonists) and have led to pediatric labeling for these drugs. This approach may likewise be used in the study of newer acid-lowering agents, such as proton pump inhibitors.

Background The objective of this study was to evaluate the accuracy of digital imaging in the diagnosis of toddler's fractures. Methods Medical records for a 9.4-year period were reviewed to locate children whose initial radiographs were interpreted as normal by a pediatric radiologist and whose subsequent bone scans or follow-up radiographs showed toddler's fractures. Radiographs from these children (ie, positive controls) and from children without toddler's fractures (ie, negative controls) were digitized to create a film bank that was reviewed by a panel of 14 physicians with various medical backgrounds. Medical records were reviewed for demographic information, findings on history and physical examination, and radiographic and laboratory tests. Results Pediatric radiology physicians correctly diagnosed 73.2 +/- 5.4% of the digitized images, as compared with pediatric emergency physicians, 66.7 +/- 6.5% and residents/fellows, 57.1 +/- 6.9%. Conclusion Digitized images may be helpful in evaluating limping children with suspected toddler's fractures, possibly eliminating the need for further diagnostic studies.

We report the presentation and management of a 25-month-old with copper sulfate ingestion. The child suffered a gastric mucosal burn, but had no evidence of systemic copper toxicity and experienced full recovery with conservative medical management. A literature review of copper sulfate poisoning is provided.

We read with interest the comments of Dr Bond regarding our recent publication1 in Pediatrics . We offer the following responses to the points that he raised. 1. Dr Bond noted that there was really no significant difference between the proportion of patients with liver failure of unknown etiology that tested positive for acetaminophen protein adducts (8 of 64) and that of patients with other causes of liver failure that tested positive for acetaminophen protein adducts (3 of 30). Therefore, he concluded that the findings were spurious. Unfortunately, his argument indicates that he ignored the adduct data …

Glucagon has been used to treat the hypotension associated with calcium channel antagonist poisoning in adult patients. We describe the successful use of glucagon in a pediatric patient poisoned with nifedipine and clonidine whose hypotension was unresponsive to fluid resuscitation, calcium chloride, and dopamine.

Famotidine, an H2 receptor antagonist, has several potential advantages over cimetidine and ranitidine. These advantages include its potency, relatively longer elimination half-life, and lack of interaction with the cytochrome P450 isoforms. Eight studies addressing the use of famotidine in paediatric patients have been published. Data from these studies demonstrate that the pharmacokinetics and pharmacodynamics of intravenous famotidine appear to be similar in both children over the age of 1 year and adults. These data support a starting paediatric dosage for intravenous famotidine of 0.5 mg/kg every 8 to 12 hours. In addition, the safety and efficacy of famotidine in the treatment of peptic ulcer disease and esophagitis in paediatric patients is supported by these studies involving over 150 children. Future studies with famotidine in paediatrics should address its disposition in children under the age of 1 year and in children with compromised renal function, as well as the bioavailability of the oral formulation.

The pharmacokinetics and pharmacodynamics of intravenous famotidine were studied in 12 children (1.1-12.9 years of age; mean weight +/- standard deviation = 27.6 +/- 21.2 kg) who were given the drug for prophylactic management of stress ulceration. After a 0.5-mg/kg infusion of famotidine, timed blood (n = 10) and urine (n = 6) samples and repeated evaluations of intragastric pH (n = 13) were obtained from each subject. Pharmacokinetic parameters were determined from curve fitting of serum concentration data. The mean (+/- SD) maximum serum concentration (Cmax) was 527.6 +/- 281.2 ng/mL, the elimination half-life (t1/2) was 3.2 +/- 3.0 hours, and the apparent steady-state volume of distribution (Vdss) was 2.4 +/- 1.7 L/kg. Plasma clearance (Cl) and renal clearance (ClR) were 0.70 +/- 0.34 L/hr/kg and 0.43 +/- 0.24 L/hr/kg, respectively. Over 24 hours, 73.0 +/- 27.3% of the dose was excreted unchanged in the urine (Fel). Pharmacodynamic analysis of gastric pH data using the sigmoid Emax model predicted that 50% of the maximal effect of famotidine (EC50) occurs at a serum concentration of 26.0 +/- 13.2 ng/mL. Children who did not have an initial intragastric pH < or = 4 did not have a significant response in pH after receiving famotidine. Although Vdss and Cl were higher in these children than those seen in adults, statistically significant relationships between these parameters and age were not observed in the study population. The pharmacodynamics and pharmacokinetics of famotidine in children older than one year of age appear to be similar to those noted in adults.

We retrospectively evaluated the clinical and laboratory findings of all patients admitted to our facility during a 6.5-year period with a history of cyclic antidepressant ingestion (CAD). Outcome parameters [admission CAD concentration, arterial pH, and corrected QT (QTc) and QRS intervals] used in adult populations to predict morbidity after CAD ingestion were applied to our study population. During the study period, 45 patients (mean +/- SD age of 11.8 +/- 5.6 years) were admitted with CAD ingestion. Conduction delays were present in 17 patients, 9 of whom had QTc intervals greater than 0.43 seconds. Seven patients had generalized seizures; 7 required mechanical ventilation; 14 had Glasgow Coma Scores of 8 or lower on presentation; and one required pharmacologic support for hypotension. In our cohort, the mean admission serum CAD concentration was 461.5 +/- 477.4 ng/mL. Correlations were found between the arterial pH, the QRS interval, the QTc interval, and the admission CAD serum concentration. In an analysis of three subsets of patients (i.e., those with seizures, coma, and respiratory insufficiency), only patients who presented with seizures were found to have a significant prolongation in the QRS and QTc intervals. Pediatric patients who have ingested CADs and present with seizures would appear to be at increased risk for having conduction delays, cardiac dysrhythmias, and, presumably, attendant morbidity and mortality associated with an ingestion.

1406 Poster Board I-428 Introduction: Patients receiving chemotherapy for malignancies are at increased risk for fever-neutropenia (F-N), which may lead to sepsis. A strategy to identify and differentiate “high-risk” patients at presentation would be of critical significance so that these patients may receive timely aggressive intervention. Conversely, early identification of “low-risk” patients allows for development of appropriate risk-stratified management. We hypothesize that certain acute phase reactants at the time of F-N presentation could be used to predict clinical outcome. Methods: Children (age 1-21 years) receiving chemotherapy for various malignancies were enrolled in this prospective study. Blood samples from F-N episodes were collected at presentation and thereafter on three consecutive days. These samples were tested for high-sensitivity C-reactive protein (hs-CRP), Soluble IL-2 receptor (s-IL2R), interleukins (IL)-1,3,6,8,10 and Tumor Necrosis Factor-alpha (TNF-a). Samples were analyzed by Luminex technology (Miliplex Cytokine Kit). Clinical outcome data were collected and correlated with the respective bio-markers at presentation. “High-risk” patients were defined as those with any one of the following criteria: prolonged hospitalization (>7 days), admission to pediatric intensive care unit, or a positive bacterial blood culture. “Low- risk” patients had none of the above criteria. Data were analyzed using SAS 9.2 software. Cluster analysis was performed on all variables using the Pearson correlation coefficient. Multivariate logistic regression analysis was performed to develop a risk based predictive model, which was validated using a Receiver Operating Characteristic (ROC) curve. Results: An interim analysis was performed on the acute phase reactant dataset that included 29 children (males 56%, females 44%) representing 51 F-N event. Univariate analysis showed that 56% of events met “high-risk” criteria while 44% of events were “low-risk”. At presentation, significant differences were observed for median values for hs-CRP, s-IL2R, IL-6, and IL-8 between the “high-risk” and the “low-risk” groups ([Table 1][1]). Cluster analysis showed a strong correlation between IL-6, IL-8, IL-10 and TNF-a. Within this cluster, IL-6 was selected as critical biomarker, since it explained most of the variability within the cluster. IL-6 was subsequently analyzed with other significant variables (hs-CRP and s-IL2R) in multivariate logistic regression. Logistic regression analysis showed that at F-N presentation, hs-CRP (p=0.02) and s-IL2R (p=0.06) were the most significant bio-markers that correlated with “high-risk” clinical course (Figure-1). Calculated “half-sample” Odds Ratio (OR) for hs-CRP was 6.87 (CI 1.35-34.96, p=0.02) and for s-IL2R was 4.94 (CI 0.94-26.01, p=0.06). After controlling for other variables in study, the analysis found that at F-N presentation, an increase in hs-CRP levels from 42 mg/L to 196 mg/L was associated with 7-fold increased likelihood of subsequent “high-risk” clinical course. Similarly, a rise in s-IL-2R from 262 pg/ml to 692 pg/ml increased the likelihood of “high-risk” by almost 5-fold. However, a rise in IL-6 from 39 pg/ml to 878 pg/ml at presentation was not statistically significant and did not predict an increased risk for complicated F-N course (OR 1.16, CI 0.72-1.88, p=0.54). This risk stratified predictive model was validated using Receiver Operating Characteristic (ROC) curve analysis (Area-Under-Curve AUC=0.84) Figure-2. Conclusion: High-sensitivity CRP and sIL-2R at presentation may represent biomarkers of “high-risk” for clinical sepsis and complicated course among children with fever neutropenia. These biomarkers should be further tested as screening tools for risk-stratification and as response variables to assess the effectiveness of interventions in children with fever neutropenia. | Bio-Marker | High Risk Median | Low Risk Median | |:----------------:| ---------------- | --------------- | | CRP mg/L | 175 | 42 | | IL-1 alpha pg/ml | 5 | 5 | | sIL-2R pg/ml | 614 | 262 | | IL-3 pg/ml | 3 | 9 | | IL-6 pg/ml | 278 | 37 | | IL-8 pg/ml | 216 | 31 | | IL-10 pg/ml | 39 | 16 | | TNF-alpha pg/ml | 8 | 5 | Table 1 Bio-marker distribution at F-N presentation. ![Figure 1][2] Figure 1 Relationship between hs-CRP, sIL-2R, IL-6 at presentation and probability of high-risk F-N. ![Figure 2][2] Figure 2 ROC curve. AUC=0.84. At cut-off probability of 0.3, sensitivity of this model is 89.7% and specificity is 59.1%. Disclosures: Mian : Arkansas Children's Hospital Research Institute (ACHRI), Little Rock, Arkansas. : Research Funding. [1]: #T1 [2]: pending:yes

Purpose Studies in animal models of acetaminophen (APAP) toxicity have reported the upregulation of cytokines, some of which are anti-inflammatory or involved in hepatocyte regeneration. To further study this relationship, cytokines were measured in children/adolescents with acute APAP overdose. Methods: ELISA measurements of IL6, IL8, IL10, and MCP1 were performed on serum samples of APAP overdose patients. Results: 76 patients (age 13.72±4.41 yrs; 64 females) were enrolled and stratified by toxicity subgroups: Grp 1 (no/mild toxicity; AST 1000 IU/L, n=13). A significant relationship was present for MCP1 (presented as median, range) (Grp 1, 628.0 pg/mL, 181.6-1800.4; Grp 2, 1137.3 pg/mL, 167.8-1808.1; Grp 3, 2777.1 pg/mL, 472.6-6291.3) and toxicity subgroups (p